1. Field of the Invention
The present invention relates to methods for parenterally delivering drugs that are unstable in aqueous media and also to compositions useful in delivering such drugs.
2. Description of the Prior Art
Intravenous techniques are the principal means of parenterally delivering drugs to humans. The delivery vehicles used in connection with such techniques are physiologically compatible aqueous solutions, such as dextrose or saline solutions. While aqueous solutions provide adequate parenteral delivery vehicles for many drugs, there are some drugs that are unstable in such aqueous media and degrade therein to useless or harmful byproducts. Some of these aqueously unstable drugs can be administered parenterally by use of a prodrug or a drug stabilizer. However, there is a remaining class of drugs that cannot be adequately stabilized in aqueous media suitable for parenteral infusion. Such drugs present serious problems in handling, storage, and delivery and are not administered parenterally, though this is often the most preferable means of delivering a drug.
Two examples of drugs that are unstable in aqueous media and, therefore, hitherto unsuitable for parenteral delivery are 5-azacytosine arabinoside (hereinafter ara-AC) and 5-azacytidine (hereinafter 5-AC), the latter also being known as 5-azacytosine riboside. Both of these drugs are promising anticancer agents. Beisler et al., "Synthesis and Antitumor Activity of 5-Azacytosine Arabinoside," J. Med. Chem., 22: 1230-34 (1979). Studies have clearly indicated, however, that 5-AC degrades at a relatively rapid rate in aqueous solutions. Benjamin et al, "Degradation Mechanism for 5-Azacytidine and Related Compounds in Aqueous Media," Amer. Pharm. Assn., 11: 60 (1981), Abstract No. 16; Benjamin, "The Chemistry of the Degradation of 5-Azacytidine and some Derivatives of 5-Azacytosine," Doctoral Dissertation, The University of Kansas, 1979. Additional studies by the inventors that are not in the prior art show ara-AC undergoes a similar degradation process. For example, ara-AC shows 10% decomposition in water in a period of 1.8 hours at 25.degree. C. (t.sub. 90 =1.8 hours). Such a rapid rate of decomposition make it impossible to manufacture and store aqueous solutions of these anticancer agents. Furthermore, this rapid degradation rate makes it very difficult if not impossible to administer an aqueous solution of 5-AC or ara-AC intravenously over a normal period of 12-24 hours. It appears that this stability problem cannot be solved by the use of stabilizers or prodrugs. Id. This led one researcher to conclude that prolonged purely aqueous intravenous infusion was the only way to clinically administer 5-AC, despite the obvious disadvantages presented by its facile decomposition into products of unknown toxicity. Beisler, "Isolation, Characterization and Properties of a Facile Hydrolysis Product of the Antitumor Nucleoside, 5-Azacytidine," J. Med. Chem., 21: 204-208 (1978).
Therefore, there is a need for a method for parenterally delivering drugs that are aqueously unstable such that the drug composition has commercially adequate storage life and yet can be made physiologically compatible for parental infusion.